"Special K" Drug on Adolescent Rats: Oxidative Damage and Neurobehavioral Impairments

Abstract

Ketamine is used in clinical practice as an anesthetic that pharmacologically modulates neurotransmission in postsynaptic receptors, such as NMDA receptors. However, widespread recreational use of ketamine in "party drug" worldwide since the 1990s quickly spread to the Asian orient region. Thus, this study aimed at investigating the behavioral and oxidative effects after immediate withdrawal of intermittent administration of ketamine in adolescent female rats. For this, twenty female Wistar rats were randomly divided into two groups: control and ketamine group (n = 10/group). Animals received ketamine (10 mg/kg/day) or saline intraperitoneally for three consecutive days. Three hours after the last administration, animals were submitted to open field, elevated plus-maze, forced swim tests, and inhibitory avoidance paradigm. Twenty-four hours after behavioral tests, the blood and hippocampus were collected for the biochemical analyses. Superoxide dismutase, catalase, nitrite, and lipid peroxidation (LPO) were measured in the blood samples. Nitrite and LPO were measured in the hippocampus. The present findings demonstrate that the early hours of ketamine withdrawal induced oxidative biochemistry unbalance in the blood samples, with elevated levels of nitrite and LPO. In addition, we showed for the first time that ketamine withdrawal induced depressive- and anxiety-like profile, as well as short-term memory impairment in adolescent rodents. The neurobehavioral deficits were accompanied by the hippocampal nitrite and LPO-elevated levels.

Figure 1

Effects of ketamine on the immediate withdrawal in adolescent female rats of 35th day until 37th day of life in the behavioral parameters: (a) traveled distance (meters) and (b) rearing number in the open-field (OF) test; (c) open arm entries (control percentage), (d) open arm time (control percentage), and (e) frequency of enclosed arm entries (number) in the elevated plus-maze. The results are expressed as the mean ± SEM (n = 10 animals per group). ^∗p < 0.05 compared to the control group; ^∗∗∗p < 0.001 compared to the control group (Student's t-test).

Figure 2

Effects of ketamine on the immediate withdrawal in adolescent female rats of 35th day until 37th day of life in the behavioral parameters: (a) immobility time (latency) and (b) climbing number. The results are expressed as the mean ± SEM (n = 10 animals per group). ^∗∗p < 0.01 compared to the control group (Student's t-test).

Figure 3

Effects of ketamine on the immediate withdrawal in adolescent female rats of 35th day until 37th day of life on short-term memory (1.5 hr). The results are expressed as the mean ± SEM. Data are shown as median (interquartile ranges) of latencies to step-down in the training and test sessions (n = 10 animals per group). ^∗∗p < 0.01 compared to the training session of the same group; ^∗∗∗p < 0.001 compared to the training session of the same group; ^##p < 0.01 compared to the test stage of the control-treated group (Mann-Whitney).

Figure 4

Effects of ketamine on the immediate withdrawal in adolescent female rats of 35th day until 37th day of life on oxidative stress on the blood samples. (a) Lipid peroxidation (malondialdehyde (MDA) concentration); (b) nitrite concentration; (c) superoxide dismutase; (d) catalase. The results are expressed as the mean ± SEM (n = 5 animals per group). ^∗∗p < 0.01 compared with the control group (Student's t-test).

Figure 5

Effects of ketamine on the immediate withdrawal in adolescent female rats of 35th day until 37th day of life on oxidative stress on the hippocampus. (a) Lipid peroxidation (malondialdehyde (MDA) concentration); (b) nitrite concentration. The results are expressed as mean ± SEM (n = 5 animals per group). ^∗p < 0.05 compared with the control group (Student's t-test).